Medulloblastoma, the most common type of primitive neuroectodermal tumor (PNET), is a malignant embryonal tumor of the nervous system, occurring mainly in children and accounting for 25% of all pediatric brain tumors. Most medulloblastoma patients are diagnosed between five and ten years of age (Louis et al. (2007) Acta Neuropathol. 114(2):97-109), and these tumors occur more often in males than in females. Few medulloblastomas occur under the age of one. These tumors arise in the cerebellum, a region of the brain that continues to develop after birth, during the first two years of human life.
Typically a childhood tumor, medulloblastoma does occur at a very low frequency in adults. Of all medulloblastomas diagnosed in the United States less than ten percent (5%) are found in adults, usually between the ages of 20-44 years. The incidence in adults sharply decreases in frequency after age 45, with very few older adults having this tumor.
A preliminary diagnosis of medulloblastoma is based on clinical symptoms and signs, supplemented by radiological investigations (neuroimaging).
Current treatment regimens for medulloblastoma depend on the age of the patient and the size and/or position of the tumor. In most cases, surgery is performed to remove as much of the tumor as possible with minimal neurological damage. In a minority of patients, the tumor has grown into the brain stem making total removal impossible. Surgery is then followed by radiation therapy to the brain and spinal cord to minimize spreading through the CSF and possible regrowth. Chemotherapy is also given to further deter the spread or regrowth of tumor cells.
The success of current treatments depends, inter alia, upon the accurate staging and subtyping of medulloblastomas. Generally, staging is dependent upon the extent of resection, evidence of tumor spread as determined by radiography, and cerebrospinal fluid (CSF) cytology and is graded according to the Chang system (M0-M4). Patients are categorized as low-risk if they undergo gross total tissue resection, with no radiographic evidence of spread, and show no malignant cells on CSF cytology.
Further classification of medulloblastoma depends upon detailed pathologic examination. Histologically, medulloblastomas are divided into five categories according to the WHO classification of tumors of the nervous system based on their morphology, the classic tumor and four variants: desmoplastic/nodular (D/N), medulloblastoma with extensive nodularity (MBEN), large cell medulloblastoma and anaplastic medulloblastoma. The last of these two are sometimes combined into a large cell/anaplastic (LC/A) category, because of their shared aggressive behavior (Kleihues et al. (2002) J. Neuropath. Exp. Neurol. 61(3):215-225).
Although significant strides have been made in diagnosing and treating these tumors, medulloblastomas remain one of the most challenging pediatric tumors, and improved survival rates have come at a significant cost with significant long-term cognitive and/or neuroendocrine adverse effects among survivors. Presently, identification of pathobiologic/molecular correlates of heterogeneous behavior that could facilitate therapeutic stratification and the application of novel therapies for children with brain tumors, including medulloblastoma, remains a major challenge in the field.
Specifically, cells within medulloblastomas that survive radiation treatment can repopulate the tumor, for example, via activation of the phosphatidylinositol-3 (PI3) kinase pathway. Thus, effective and optimal techniques to identify, type/characterize, and then target these cells to eliminate the tumor in its entirety while sparing the rest of the brain are still needed. In order for the appropriate therapy to be effectively applied, it is necessary that the type of medulloblastoma present in patients be determined as soon as possible. Therefore, the development of novel ways to type medulloblastomas that may benefit from a distinct therapeutic protocol and, thus improve outcome of patients with these specific medulloblastomas, are also urgently needed.